Process for producing amide derivatives and intermediate compoun

Details Process for producing amide derivatives and intermediate compoun Process for producing amide derivatives and intermediate compoun

1998-05-19

2000-09-19

Kumar, Shailendra

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549519, 549551, C07D30102, C07D30304

Patent

active

06121468&

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel method for producing a compound of the formula [XVI] ##STR2## wherein Me is methyl, Bu-t is t-butyl and Ph is phenyl, which is useful as a treatment drug of HIV-related diseases as a result of its inhibitory action on proteases derived from viruses, various novel intermediate compounds useful for producing said compound [XVI], and to the method for production thereof. These intermediate compounds can be used not only for the production of the above-mentioned compound [XVI] but also for the production of various other compounds.


BACKGROUND ART

The above-mentioned compound [XVI] useful as an HIV protease inhibitor is known as described in WO095/09843. This compound [XVI] has been conventionally produced from serine as a starting material by increasing carbon and through numerous other steps inclusive of stereoselective reduction of carbonyl group. Such conventional production method is extremely complicated and inefficient, since it requires expensive starting materials and constant low temperature conditions for reactions. Accordingly, there remain many problems to be solved before the conventional synthetic method is actually put to industrial practice.
In addition, 2,2-dimethyl-6-amino-1,3-dioxepan-5-ol which is described in, for example, U.S. Pat. No. 4439613 is an intermediate for producing a compound useful as an X ray contrast medium, and even though the compound obtained is a racemate, resolution of the racemate itself by a method such as recrystallization has been extremely difficult. Moreover, this U.S. patent does not suggest production of a specific enantiomer of the present invention.
Accordingly, an object of the present invention is to provide a method for stereoselectively and extremely efficiently producing the above-mentioned compound [XVI] useful as an HIV protease inhibitor upon solution of the above-mentioned problems. Another object of the present invention is to provide a novel intermediate compound useful for producing said compound, and a production method thereof.


DISCLOSURE OF THE INVENTION

The present inventors have made intensive studies in an attempt to achieve the above-mentioned objects, and found that a step comprising acetalating or ketalating (z)-2-butene-1,4-diol, and epoxidation of the obtained compound to give a 3,5,8-trioxabicyclo[5.1.0] octane derivative, which is followed by an epoxy ring-opening reaction using a chiral amine, leads to a stereospecific (5R,6S)-6-substituted amino-1,3-dioxepan-5-ol derivative or an enantiomer thereof, from which a compound of the following formula [XV], that is, a compound inclusive of the aforementioned compound [XVI] useful as an HIV protease inhibitor, can be extremely efficiently produced stereoselectively through various other steps, which resulted in the completion of the present invention.
That is, the present invention provides the following (1) to (14). formula [VII] ##STR3## wherein R.sup.1 and R.sup.2 are the same or different and each is a hydrogen atom, an alkyl or an aryl, or R.sup.1 and R.sup.2 combinedly form a cycloalkyl ring together with the adjacent carbon atom, and R.sup.4 is an amino-protecting group, an enantiomer thereof and a salt thereof. ##STR4## wherein R.sup.1 and R.sup.2 are the same or different and each is a hydrogen atom, an alkyl or an aryl, or R.sup.1 and R.sup.2 combinedly form a cycloalkyl ring together with the adjacent carbon atom, and R.sup.4 is an amino-protecting group, an enantiomer thereof and a salt thereof. formula [VIII] ##STR5## wherein R.sup.1, R.sup.2 and R.sup.4 are as defined above, and an enantiomer thereof, comprising isomerizing a (5R,6S)-6-substituted amino-1,3-dioxepan-5-ol derivative of the formula [VII] ##STR6## wherein R.sup.1, R.sup.2 and R.sup.4 are as defined above, or an enantiomer thereof into a 5-membered ring in the presence of an acid. formula [VIII] ##STR7## wherein R.sup.1, R.sup.2 and R.sup.4 are as defined above, and an enantiomer thereof, comprising protecting an amino group of a (5R,6S)-6-amino-1,3-d

REFERENCES:
patent: 5733906 (1998-03-01), Jungheim et al.
Tetrahedron, vol. 51, No. 20, May 1995, pp. 5877-5890.

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